TEMPO-Me: An Electrochemically Activated Methylating Agent

Article abstract of DOI:10.1021/jacs.9b08634

Bench- and air-stable 1-methoxy-2,2,6,6-tetramethylpiperidine (TEMPO-Me) is relatively unreactive at ambient temperature in the absence of an electrochemical stimulus. In this report, we demonstrate that the one-electron electrochemical oxidation of TEMPO-Me produces a powerful electrophilic methylating agent in situ. Our computational and experimental studies are consistent with methylation proceeding via a S_N2 mechanism, with a strength comparable to the trimethyloxonium cation. A protocol is developed for the electrochemical methylation of aromatic acids using TEMPO-Me.

Full text of DOI:10.1021/jacs.9b08634

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Article
TEMPO–Me: An Electrochemically Activated Methylating Agent
Philip L. Norcott, Chelsey L. Hammill, Benjamin B. Noble, Johnathon
C. Robertson, Angus Olding, Alex C. Bissember, and Michelle L. Coote
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08634 • Publication Date (Web): 04 Sep 2019
Downloaded from pubs.acs.org on September 4, 2019
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TEMPO–Me: An Electrochemically Activated Methylating Agent
Philip L. Norcott,† Chelsey L. Hammill,† Benjamin B. Noble,† Johnathon C. Robertson,‡ Angus
Olding,‡ Alex C. Bissember,*,‡ Michelle L. Coote*,†
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†ARC Centre of Excellence for Electromaterials Science & Research School of Chemistry, Australian National University, Canberra ACT, 2601, Australia
‡School of Natural Sciences – Chemistry, University of Tasmania, Hobart TAS, 7001, Australia
ABSTRACT: Bench- and air-stable 1-methoxy-2,2,6,6-tetramethylpiperidine (TEMPO–Me) is relatively unreactive at ambient
temperature in the absence of an electrochemical stimulus. In this report, we demonstrate that the one-electron electrochemical
oxidation of TEMPO–Me produces a powerful electrophilic methylating agent in situ. Our computational and experimental studies
are consistent with methylation proceeding via a SN2 mechanism, with a strength comparable to the trimethyloxonium cation. A
protocol is developed for the electrochemical methylation of aromatic acids using TEMPO–Me.
INTRODUCTION
Methylation is a ubiquitous, fundamental process in biological
and chemical systems.1-2 In biology, methylation can be
achieved through enzymatic methyl transfers often involving S-
adenosyl methionine.3 In chemical synthesis, both electrophilic
and nucleophilic (including radical) sources of the methyl group
4-6
are commonly deployed in a variety of contexts.1,
Electrophilic methylation is typically achieved using a reagent
bearing a highly stabilized leaving group.7 Consequently, many
established methylating agents, such as iodomethane, dimethyl
sulfate, methyl triflate or diazomethane (or its derivatives)
exhibit acute toxicity. Some of these reagents are also
particularly volatile and/or potentially explosive.8 Safer and
“greener” alternatives have arisen, such as dimethyl carbonate,
but these are often less reactive.9
In 2018, we demonstrated that an electrochemically-
promoted one-electron oxidation of styrene-derived
a
alkoxyamine results in rapid and irreversible mesolytic bond
cleavage, producing a stable nitroxide radical and a carbocation
at ambient temperature, rather than a carbon-centered radical
(Scheme 2a).16 Similar approaches for the generation of
stabilized (e.g., benzylic) cations have also been reported using
photoredox catalysis (Scheme 2b),17-18 or conventional single-
electron chemical oxidants, and have been used for alkylation
procedures operating via SN1 reactivity.19 This reveals that
alkoxyamines capable of providing stabilized carbocation
intermediates are prone to spontaneous fragmentation under
oxidative conditions.17-20 However, the formation of
unstabilized carbocations from alkoxyamines via mesolytic
cleavage is more challenging due to the higher C–O bond
dissociation energy of the alkoxyamine radical cations.17, 21-22
The development of new compounds that can serve as
reactive, in-situ-generated methylating agents offers many
advantages. Indeed, various reagents such as N,N-
dimethylformamide dimethyl acetal or trimethyl orthoacetate
have been used in this capacity.10-11 Safer strategies have also
been developed in which powerful alkylating species such as
diazomethane are prepared and reacted in situ,12-13 thus
eliminating the need to isolate and handle hazardous reagents.
In these cases, chemical reagents and/or inputs of thermal
energy provide active methylating species in solution.
Identifying alternative strategies that can provide access to
highly reactive methylating agents from latent, relatively non-
toxic precursors under mild conditions remains of fundamental
and practical interest.
We have previously shown that the oxidized form of 1-
methoxy-2,2,6,6-tetramethylpiperidine (TEMPO–Me, 1) is
resistant to direct mesolytic cleavage.22 However, in this work
we demonstrate that the electrophilicity of this radical cation
can still be harnessed in the form of SN2 reactivity. Ultimately,
we define a new strategy for the in situ electrochemical
generation of an active methylating agent (1+•) from latent,
relatively benign TEMPO-Me (Scheme 2c). In this process, the
use of electrochemistry obviates the need for transition metal
catalysts or stoichiometric chemical oxidants.
Scheme 2. (a) Electrochemically-promoted mesolytic bond cleavage of
alkoxyamines. (b) Photoredox-catalyzed alkylation via mesolytic bond
cleavage of alkoxyamines. (c) Electrochemical methylation employing
TEMPO–Me.
Alkoxyamines feature heat-labile C–O bonds, but are
typically stable at ambient temperature.14 At elevated
temperatures, thermally-induced homolytic bond cleavage of
certain alkoxyamines can provide a persistent nitroxide and
carbon-centered radical (Scheme 1). This property of
alkoxyamines has led to their prolific use in polymer chemistry
and materials science.15
Scheme 1. Conventional homolytic reactivity of alkoxyamines.
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together, these data are consistent with a bimolecular
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substitution reaction between the electrochemically-formed
radical cation 1+• and a nucleophile to deliver a methylated
product (Figure 1e). Certainly, the persistence of radical cation
1+• in solution (in the absence of a nucleophile) strongly
suggests that that nucleophilic substitution does not proceed via
a SN1 mechanism.
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RESULTS AND DISCUSSION
Synthesis of TEMPO-Me. In order to explore the utility of
TEMPO–Me (1) as a potential methylating agent, a simple and
efficient synthesis was essential. While this alkoxyamine has
often been identified as a product in radical trapping
experiments, there are few reports of its isolation and extensive
characterization.23-26 Using Fenton-type chemistry we were able
to achieve a high-yielding multi-gram synthesis of 1 from
TEMPO (Scheme 3).27 We found that the product was stable to
flash column chromatography and no degradation was observed
after storage under air, at ambient temperature and in the
presence of natural light over ca. 6 months.
Figure 1. Cyclic voltammogram of a solution of substrate (2 mM)
and Bu4NClO4 (0.1 M) in MeCN; Ag/AgCl reference electrode.
Scan rate: 500 mV.s-1. Solid line = scan 1, dotted line = scan 2. (a)
TEMPO–Me (1). (b) TEMPO–Me + pyridine (4 equiv). (c) N-
methylpyridinium iodide. (d) TEMPO. (e) Oxidation of TEMPO–
Me (1) and subsequent reaction with pyridine.
Scheme 3. Synthesis of TEMPO–Me (1).
Theoretical Mechanistic Studies. Recently, we used theory
and experiment to study the effect of solvent and electrolyte on
the C–O fragmentation of another alkoxyamine that also lacks
strong stabilizing functional groups, 1-iso-propoxy-2,2,6,6-
tetramethylpiperidine (TEMPO–iPr).29 We found that cleavage
could be promoted to varying extents by some coordinating
–
solvents (THF, MeNO2, MeCN) and electrolyte anions (NO3 ,
Cyclic Voltammetry Studies. When analyzed by cyclic
voltammetry, TEMPO-Me (1) displayed a reversible redox
couple at a potential of +1.22 V vs. Ag/AgCl in MeCN,
consistent with the formation of the radical cation 1+• in the
absence of any observable C–O bond cleavage (Figure 1a).
However, when pyridine (4 equiv) was added, the oxidation of
TEMPO–Me (1) was found to be irreversible, indicating a
subsequent chemical transformation (Figure 1b). Specifically,
signals consistent with the concomitant production of TEMPO
and an N-methylpyridinium species under these conditions
were evident after the first anodic scan and persisted in
subsequent scans, typical of an ECirrevE mechanism of C–O
cleavage.16 The assignment of these additional signals was
supported by comparison of the cyclic voltammograms of N-
methylpyridinium iodide28 (Figure 1c) and TEMPO (Figure 1d)
measured separately under identical conditions. When taken
–
–
–
HSO4 , TfO–, ClO4 , BF4 ), or inhibited under non-coordinating
conditions (Bu4NPF6 in CH2Cl2). Theoretical calculations
identified SN2 transition states for the cleavage of TEMPO–iPr
by coordinating species, with rate coefficients consistent with
those fitted to the experimental cyclic voltammograms. A
similar mode of reactivity can be envisaged between TEMPO–
Me and pyridine. This is consistent with the fact that, while the
use of various coordinating solvents or anions made no
observable difference to the voltammogram of 1, a more
nucleophilic additive (pyridine) was able to cause reactivity.
With this in mind, we examined the SN2 transition state
energies of a selection of common methylating agents with
pyridine as a reference nucleophile, which allowed us to
compare the respective methylation strengths of these
molecules with methoxyamine radical cation 1+• (Table 1). We
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found that 1+• gave lower activation energies and more
the aforementioned reaction with pyridine (see Supporting
Information for full voltammograms).
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favorable overall reaction energies than methyl triflate and was
comparable to the trimethyloxonium cation – both generally
recognized as powerful electrophiles. This suggested that
species 1+• could serve as a potent methylating agent.
Table 1. Comparison of (TEMPO–Me)+• (1+•) with common methylating
agents, using pyridine as a reference nucleophile.a
When these findings were applied on a preparative scale
(0.5 mmol) using the standardized IKA Electrasyn 2.0 cell (10
mL) and graphite electrodes, it was found that benzoic acid
could be converted to methyl benzoate in the presence of either
potassium carbonate or cesium carbonate under a constant
current of 10 mA, albeit in low isolated yields (Table 2, entries
1 and 2). In the presence of these heterogeneous bases,
significant deposition on the cathode was observed which, if the
cell polarity was not regularly alternated, completely inhibited
the reaction. In contrast, the use of the homogeneous, non-
nucleophilic base, 2,6-di-tert-butyl-pyridine, increased the
yield and did not require alternating cell polarity (entry 3).
Cyclic voltammetry studies suggest that this base does not react
with 1+• directly, however, less hindered pyridine bases such as
2,6-lutidine were found to be competitive nucleophiles (see
Supporting Information).
Electrophile
ΔG‡
ΔGrxn
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MeOTf
73.2
67.7
66.5
31.5
−119.6
−121.3
−124.9
−254.7
Me3O+
(TEMPO–Me)+•
+
MeN2
a in kJ.mol-1, calculated using G3(MP2,CC)(+)//M06-2X/6-31+G(d,p).
Reaction Optimization. As a case study of the feasibility of 1
as a methylating agent in a synthetically useful setting on a
preparative scale, we then investigated the electrochemical
methylation of carboxylic acids to produce their corresponding
methyl esters. In cyclic voltammetry experiments, benzoic acid
was insufficiently nucleophilic to react with 1+• to an
appreciable extent. In contrast, the benzoate anion caused C–O
fragmentation to produce TEMPO in an analogous fashion to
The use of acetonitrile as solvent afforded better results than
dichloromethane (entry 4), while THF and DMSO both failed
to give any isolable product, as much higher solution resistances
were observed (entries 5 and 6). Changing the electrolyte from
Bu4NBF4 to either Bu4NPF6 or Bu4NClO4 gave enhanced
yields, with the latter providing a 51% yield (entries 7 and 8).
The yield of methyl benzoate was essentially
Table 2. Electrochemical methylation of benzoic acid using TEMPO–Me: Influence of reaction parameters.a
Electrolytic
Conditions
Isolated
Entry
Electrolyte
Solvent
Base (eq.)
Cs2CO3
F.mol-1
Yield (%)b
1
2
Bu4NBF4
Bu4NBF4
Bu4NBF4
MeCN
MeCN
MeCN
(1.1)
(1.1)
(1.1)
10 mA
12.2
12.2
12.2
0 (13)c
0 (21)c
K2CO3
10 mA
2,6-(t-
Bu)2C5H3N
10 mA
3
37
4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NPF6
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
Bu4NClO4
CH2Cl2
THF
2,6-(t-Bu)2C5H3N
2,6-(t-Bu)2C5H3N
2,6-(t-Bu)2C5H3N
2,6-(t-Bu)2C5H3N
2,6-(t-Bu)2C5H3N
2,6-(t-Bu)2C5H3N
2,6-(t-Bu)2C5H3N
None
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(0.25)
(0.10)
-
10 mA
10 mA
10 mA
10 mA
10 mA
10 mA
10 mA
10 mA
5 mA
12.2
12.2
12.2
12.2
12.2
12.2
12.2
12.2
6.1
22
0
5
6
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
0
7
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91d
8
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14
2,6-(t-Bu)2C5H3N
2,6-(t-Bu)2C5H3N
2,6-(t-Bu)2C5H3N
(0.10)
(0.10)
(0.10)
15 mA
10 mA
18.3
6.7
a Reactions consisted of 2a (0.5 mmol), 1 (0.55 mmol, 1.1 eq.), and base (stated equivalents) in an electrolyte solution (10 mL; 0.1 M)
electrolyzed in a 10 mL undivided cell at room temperature open to air for 18 h using an IKA Electrasyn 2.0 and two graphite electrodes,
unless otherwise specified. b Yield with respect to 2a. c Yield obtained when the cell polarity was reversed every 10 minutes. d 2.0 eq. of 1.
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unchanged when the loading of 2,6-di-tert-butyl-pyridine was
lowered to catalytic levels (entries 9 and 10). There have been
reports of the electrochemical reduction of protonated pyridine
species for the production of H2,30-31 suggesting that a reduction
process at the cathode may play a role to regenerate the base in
our methylation protocol. In the absence of base, the reaction
proceeded in greatly reduced yield (entry 11).
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used (Table 2, entry 14), methyl p-toluate (3b) and methyl 4-
fluorobenzoate (3c) were isolated in 97% and 60% yields,
respectively. 4-Fluorobenzoic acid could be prepared in a
higher yield using the alternative potentiostatic procedure (as in
Scheme 4b). 4-(tert-Butyl)benzoic acid (2d) was also
methylated in good yield, in addition to the ortho-substituted
substrate 2-phenylbenzoic acid (2e). The heteroaromatic acid,
thiophene-2-carboxylic acid was efficiently converted into ester
3f, while monoethyl phthalate and 2-naphthoic acid also
provided respective products 3g and 3h.
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As expected, variations in the electrolytic conditions had a
pronounced effect on the efficiency of the reaction. Employing
a lower 5 mA current decreased the reaction rate and yield
(entry 12), while at 15 mA, an increase in decomposition greatly
reduced efficiency (entry 13). Ultimately, using 2 equivalents
of 1 was optimal, and furnished ester 3a in 91% yield (entry
14). Alternatively, under potentiostatic operation and slightly
different reaction conditions, a good yield of methyl benzoate
could still be obtained in 8 h (Scheme 4b).
9
All of these reactions could be conducted in an undivided
cell, however, for substrates featuring functional groups more
susceptible to electroreduction, the methylation procedure was
performed in a simple divided cell setup, detailed in the
Supporting Information, Appendix S3. For instance, p-
nitrobenzoic acid gave a complex mixture of products when
reacted in an undivided cell. This presumably derived from the
reduction of the nitro group. However, when reacted in a
divided cell, this compound could be methylated to afford ester
3i. In these cases, cesium carbonate was found to be the most
efficient base and the catalytic activity of 2,6-di-tert-butyl-
pyridine was inhibited. Under these conditions, ketone-
containing substrate 2j was compatible and trans-cinnamic and
phenylpropiolic acids could be methylated to give 3k and 3l,
respectively.
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Scheme 4. Conventional chemical oxidants or photoredox catalysis do not
facilitate the methylation of benzoic acid.
Electrochemistry was crucial to facilitating the methylation
of benzoic acid (Scheme 4a, b). Chemical oxidants such as ceric
ammonium nitrate (CAN),19 m-chloroperbenzoic acid
(mCPBA),27 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ),
and (diacetoxyiodo)benzene (PIDA) proved to be ineffective in
enabling this transformation (Scheme 4c). In each case,
compound 1 was essentially unreacted and methyl benzoate
was not formed. We were also unable to promote this reaction
via photoredox catalysis. For example, employing either
[Ru(2,2’-bipyrazyl)3]2+ (Eox = +1.58 V vs. Ag/AgCl in MeCN)
or [Cu(bathocuproine)(xantphos)]+, (Eox = +1.44 V vs.
Ag/AgCl in MeCN) did not provide product 3a (Scheme 4d).17,
Figure 2. Electrochemical methylation of carboxylic acids
employing TEMPO–Me. a These reactions were also conducted
under the alternative potentiostatic conditions: Scheme 4b; 1
mmol of 2. Isolated yields of 3a, 3b, and 3c were 80%, 81%
and 83% respectively.
32
This is consistent with previous observations noting the
difficulty in generating less stabilized carbocations from
alkoxyamines via photoredox catalysis.17 Thus, these results
highlight the unique capacity for electrochemistry to promote
reactivity that is otherwise unattainable.
While high yields were obtained in specific cases, we
envisage that more refined divided cell conditions could
increase the efficiency and scope of this process to an even
greater extent. Similarly, the utilization of electrochemical flow
systems would undoubtedly allow fine-tuning and optimization
Reaction Scope. Following this, we explored the scope of the
reaction with a range of electronically- and sterically-varied
carboxylic acids (Figure 2). When the optimal conditions were
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of these transformations,33-34 this is however beyond the scope
related compounds within the context of chemical alkylation
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of this report. Further improvements may also lie in the
development of an analogue of alkoxyamine 1 that is more
susceptible to electrochemical oxidation. This may increase the
scope of this methylation process to a wider range of
nucleophiles which are currently challenging when competitive
oxidation occurs. In this regard, recent findings will be
instructive.35-36 Through structural changes it may also be
beneficial to adjust the difference in the reduction potential of
the alkoxyamine and the corresponding nitroxide, as our
investigations revealed that the addition of excess TEMPO
inhibited the methylation (see Appendix S2).
are underway.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
General experimental, synthetic methods and characterization data,
electrochemical setup, cyclic voltammetry data and computational
methods and data (PDF).
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AUTHOR INFORMATION
Corresponding Author
Deuterium Labelling. As discussed earlier, mechanistic
studies on closely related systems provide further evidence that
supports the operation of a SN2 mechanism in this methylation
process.29 However, the oxidative cleavage of N-
methoxyamines mediated by mCPBA in dichloromethane has
been reported.27 The authors propose that this transformation
proceeds via a Cope-type elimination mechanism in which the
methyl substituent is liberated as formaldehyde. In order to
exclude the possibility that the reaction proceeds via the
deprotonation of radical cation 1+• to afford a transient carbene
species (or formaldehyde), the deuterated analogue TEMPO–
CD3 (d3–1, >99% D incorporation) was prepared from d6-
DMSO. When d3–1 was reacted with p-nitrobenzoic acid (2i)
under the standard conditions, no evidence of H/D exchange
was observed in benzoate d3–3i as judged by mass spectrometry
and NMR spectroscopy (Scheme 5). Beyond the mechanistic
implications of this experiment, this also demonstrates the
capacity of this chemistry to facilitate d3-methylation with
isotopic retention.
* Email: michelle.coote@anu.edu.au
* Email: alex.bissember@utas.edu.au
Author Contributions
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the
manuscript.
Funding Sources
Australian Research Council (FL170100041, CE140100012).
ACKNOWLEDGMENT
The authors acknowledge a Georgina Sweet Australian Research
Council (ARC) Laureate Fellowship (M.L.C.), the ARC Centre of
Excellence for Electromaterials Science (M.L.C), the Australian
government for a Research Training Program Scholarship (C.L.H,
J.C.R.), Collier Charitable Fund Grant (A.C.B.), and generous
supercomputing time from the National Computational
Infrastructure (M.L.C.).
Scheme 5. Selective d3-methylation with TEMPO–CD3.
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a one-electron
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cation 1+•) to be generated and reacted in situ. These
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resistance to mesolytic cleavage is not necessarily a hindrance
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carboxylic acids. Our computational and experimental studies
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